Strokes Follow Xarelto to Warfarin Switch

Action Points

Note that the ROCKET AF trial found an increased risk of stroke after rivaroxaban was discontinued during the transition to warfarin in patients with nonvalvular atrial fibrillation.

Note that the rate of strokes and blood clots was not different if either rivaroxaban or warfarin was discontinued temporarily or permanently during the trial period.

Atrial fibrillation patients who transition from rivaroxaban (Xarelto) to a vitamin K antagonist may have an increased risk of stroke, a subanalysis of the ROCKET-AF trial found.

At the completion of the trial, the risk of stroke for those moving off rivaroxaban was 6.42 per 100 patient-years compared with 1.73 per 100 patient-years for those on warfarin, Jonathan P. Piccini, MD, from Duke University Medical Center, and colleagues reported during an American Heart Associations's Emerging Science Series webinar.

But patients who temporarily or permanently stopped rivaroxaban or warfarin during the trial had similar rates of stroke or non-central nervous system embolism, according to Piccini.

"These findings argue for continued anticoagulation coverage if patients are transitioned from one anticoagulant to another," Piccini said.

Patients on oral anticoagulants are sometimes instructed to stop taking the drugs temporarily before surgery or permanently because of side effects. However, it's unclear how to provide optimal anticoagulation coverage during periods of transition, Piccini said.

In the original ROCKET-AF trial, rivaroxaban was found to be noninferior to warfarin in preventing stroke and other blood clots in more than 14,000 patients with moderate to high-risk nonvalvular atrial fibrillation. Patients also had no greater risk of bleeding.

Because of the trial results, the FDA approved rivaroxaban in this patient population. However, the FDA included a warning in the prescribing information about increased rates of stroke and blood clots after discontinuing rivaroxaban.

In an effort to determine the risk, Piccini and colleagues evaluated three clinically relevant situations:

Temporary interruption of 3 days or more -- examining events 3 days after interruption until 3 days after resumption

Early permanent discontinuation -- examining events from 3 to 30 days

Completion of the study (blinded transition to open label) -- examining events from 3 to 30 days

There were 8,245 patients with a temporary interruption (more common in the warfarin arm), with a median duration of 6 days, followed by 4,895 patients who permanently stopped taking either drug (equal percentage among both arms), and 9,239 who transitioned to open label therapy (more than 90% of them to vitamin K antagonists), again equal percentage among both arms.

The three most common reasons for temporary interruption were a surgical or invasive procedure, a nonbleeding adverse event, and subject error.

The three most common reasons for early permanent cessation were a nonbleeding adverse event, consent withdrawn, and the investigator suspected the clinical efficacy endpoint had been reached.

What Piccini and colleagues found were no differences in stroke or blood clots for temporary interruptions, permanent discontinuation, and the combination of temporary and permanent cessation.

However, there was a significantly greater chance of a primary event, particularly stroke, in those transitioning from rivaroxaban at the end of the study. There was also a significantly greater risk for the secondary composite endpoint (including strokes, heart attack, and vascular death) for those transitioning from rivaroxaban.

And finally, the rivaroxaban arm had significantly more major bleeding events at the end of the study, while there was no difference in the temporary or permanent cessation groups.

Upon further investigation, researchers found that at 3 months post transition to open label therapy, 81% of the warfarin group had a therapeutic international normalized ratio (INR), compared with just 49% of the rivaroxaban group, which could explain the higher event rate in the study drug arm, Piccini said.

"The equipoise that was present between the two arms during interruption or permanent cessation was no longer present at the end of the study" when the rivaroxaban group transitioned from the short-acting study drug to the long-acting warfarin, he said.

Moderator Elliot Antman, MD, from Harvard Medical School in Boston, said that this has profound implications for the design of clinical trials.

In everyday practice, however, the need to transition from an oral anticoagulant is "relatively rare," said panelist Jeffrey I. Weitz, MD, from McMaster University in Ontario.

He said there are no prospective data from the trial to guide the change, but "clinicians can overlap rivaroxaban with warfarin perhaps for the first 48 hours of warfarin therapy, followed by careful INR monitoring."

Alternatively, clinicians can stop rivaroxaban and enact some form of bridging therapy, whether it's low-molecular weight heparin or some other therapy.

"But one of the key points is that no matter what strategy is chosen, INR monitoring is essential," Weitz said.